Comparative complete scheme and booster effectiveness of COVID‐19 vaccines in preventing SARS‐CoV‐2 infections with SARS‐CoV‐2 Omicron (BA.1) and Delta (B.1.617.2) variants: A case–case study based on electronic health records

Abstract Background Information on vaccine effectiveness in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub‐lineages) VOC according to vaccination exposure (primary or booster). Methods We developed a case–case study using data on RT‐PCR SARS‐CoV‐2‐positive cases notified in Portugal during Weeks 49–51, 2021. To obtain measure of comparative vaccine effectiveness, we compared the odds of vaccination in Omicron cases versus Delta using logistic regression adjusted for age group, sex, region, week of diagnosis, and laboratory of origin. Results Higher odds of vaccination were observed in cases infected by Omicron VOC compared with Delta VOC cases for both complete primary vaccination (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.8 to 2.4) and booster dose (OR = 5.2; 95% CI: 3.1 to 8.8), equivalent to reduction of vaccine effectiveness from 44.7% and 92.8%, observed against infection with Delta, to −6.0% (95% CI: 29.2% to 12.7%) and 62.7% (95% CI: 35.7% to 77.9%), observed against infection with Omicron, for complete primary vaccination and booster dose, respectively. Conclusion Consistent reduction in vaccine‐induced protection against infection with Omicron was observed. Complete primary vaccination may not be protective against SARS‐CoV‐2 infection in regions where Omicron variant is dominant.


| BACKGROUND
The Omicron (BA.1) SARS-CoV-2 variant first reported in South Africa on November 24, 2021, 1 has been designated by the World Health Organization 2 as a variant of concern (VOC), as it presents several mutations associated with increased transmissibility and higher risk of reinfection. 3,4 The Omicron (BA.1) variant yields an S-gene target failure (SGTF) signal (due to the deletion Δ69-70 in the Spike protein) in some polymerase chain reaction (PCR) tests (e.g., TaqPath COVID-19, ThermoFisher, Waltham, MA, USA), which can be used as a proxy for Omicron detection and differentiation from the circulating Delta (B.1.617.2 and sub-lineages) variant (in which the Δ69-70 is rarely detected). 5 The Omicron had a swift rise in Europe becoming dominant in a few weeks in England, Scotland, and Denmark, 6  The first studies on neutralization assays revealed an extensive but incomplete escape of Comirnaty BNT162b2-elicited neutralization, 9 but booster dose increased the neutralization. 10 These preliminary in vitro results were confirmed by the first vaccine effectiveness (VE) studies in England and Scotland 11,12 for symptomatic infections for both complete primary vaccination schemes and booster doses. The UK study estimated a reduction of VE for symptomatic infection with the Omicron with no effect for two ChAdOx1 (AstraZeneca) doses and 8.8% (95% confidence interval [CI]: 7.0 to 10.5) at 25 or more weeks post dose 2 of BNT162b2 (Comirnaty). 11 Another study in Denmark found similar results with reduced VE against Omicron infection compared with Delta for two doses of BNT162b2 (Comirnaty) and mRNA-1273 (Moderna), with an increase in VE after a booster dose. 13  The target population included individuals resident in mainland Portugal aged 12 or more years old (eligible for vaccination at the time of the data collection) 18 with positive RT-PCR notified to the mandatory National Epidemiological Surveillance Information System (SINAVE) during the study period. To evaluate the effect of primary vaccination, data were restricted to individuals without a history of previous SARS-CoV-2 infection or vaccine booster. To access the effect of the booster dose, we restricted the sample to those aged 50 or more years old because younger age groups were not yet eligible for the booster vaccination at the time of the study and to those without a history of previous SARS-CoV-2 infection. 18 We excluded individuals with missing data on National Health Service User number, age, sex, place of residence, or diagnosis date from all analyses.   To avoid small sample size bias, we will not present estimates for vaccine exposure categories with sample size n < 20.

| Statistical analysis
Characteristics of participants infected with Omicron and Delta VOC were compared using the chi-square test. Logistic regression adjusted for age group, sex, region of residence, week of diagnosis, and laboratory of origin was used to estimate adjusted odds of complete/ boosted vaccination in Omicron-infected cases compared with Deltainfected SARS-CoV-2 cases. If the odds of vaccination between Omicron and Delta cases are similar, we expect to obtain an odds ratio (OR) = 1, a proxy of no difference in VE. If the odds of vaccination among Omicron cases are higher compared with Delta, we expect an OR to be greater than one (OR > 1) and as such lower VE against Omicron compared with Delta VOC. In contrast, an OR smaller than one (OR < 1) will indicate higher VE against Omicron in comparison with Delta VOC.
We also provide estimates of VE against the Omicron laboratoryconfirmed infection (either symptomatic or asymptomatic) for the complete primary vaccination scheme and the booster dose by combining previously published VE estimates against Delta and OR estimated in this study using the following formula:  To account for uncertainty from the CIs around point estimates, we used Monte Carlo simulations, considering that the logarithm of OR caseÀcase and the logarithm of (1 À VE Delta ) are normally distributed.
A more detailed description of Monte Carlo simulations is provided in the supporting information.

| Sensitivity analysis
To assess the bias of misclassification error associated with the SGTF method, we included only cases identified exclusively through WGS.
We also restricted the analysis to the samples with Ct values below 25

| Main results
We  the population aged 50 or more years old without previous SARS-CoV-2 infection (Table 3). Cases' characteristics by vaccination status are shown in the supporting information.
This relative reduction in the protection conferred by the booster dose was more pronounced compared with the one observed for complete vaccination in this age group (OR = 1.7; 95% CI: 1.1 to 2.6).
In sensitivity analysis, restriction to cases with Ct < 25 led to a reduction in OR estimates for both complete primary vaccination vaccination and 62.7% (95% CI: 35.7% to 77.9%) for ≥10 weeks following the subsequent booster with Comirnaty vaccine.  Investigation; writing-review and editing.

CONFLICT OF INTEREST STATEMENT
Dr. Peralta-Santos reports to participate as a speaker in scientific meetings sponsored by Pfizer. Other authors report no potential conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of the study were made available under a license that the author does not have permission to share.
Requests to access the raw data should be directed to the data owner, the General Directorate of Health.

ETHICS APPROVAL STATEMENT
The genomic surveillance of SARS-CoV-2 in Portugal is regulated by